Parasitic diseases are major causes of morbidity and mortality throughout the world. The outcome of many parasitic infections depends on whether or not an infected host mounts the correct type of helper T cell response against the invading microbe. T helper-1 (Thl) cells are critical for protection against intracellular protozoa, and T helper-2 (Th2) cells are critical for expulsion of intestinal helminths. Mature Thl and Th2 cell subsets are thought to arise from a common naive progenitor. How states of gene activity are acquired and transmitted to daughter cells are critical issues that currently remain unresolved. This proposal investigates the mechanisms controlling how highly polarized immune responses against parasitic pathogens develop. Evidence is offered in support of a model that the molecular signatures of Thl and Th2 cells, the specific effector cytokines that mediate control of the parasites, are regulated by gene silencing. In naive progenitor cells, effector cytokine genes appear to exist in a non-permissive structure, which is determined by methylation of cytosines in DNA and specific modifications of histone tails. The non- permissive structures appear to be plastic, giving way to more active structures in some daughter cells. This proposal uses genetic and biochemical approaches to try to define how a model gene, interleukin-4 (IL-4), becomes re-assembled into an active structure as a naive cell becomes a Th2 cell. It also examines how gene silencing of IL-4 is maintained in Thl cells. The proposal also tests the consequences of defective gene silencing when hosts are confronted with parasitic infections in vivo. Successful execution of the 3 specific aims of this proposal should provide novel insight into the way that helper T cells mature, and novel strategies to defend humans against parasitic invaders.